NK cells protect hosts against viral pathogens as well as transformed cells. IL-15 is thought to play a critical role in NK cell development, and may mediate these effects through binding to its high affinity receptor, IL-15Ra. By generating and characterizing mice deficient for IL-15Ra, and analyzing radiation bone marrow chimera derived from these mice, we have obtained data suggesting that IL-15Ra plays critical roles in regulating mature NK cell homeostasis and NK cell activation, as well as NK cell development. Surprisingly, the mechanism by which IL-15Ra performs these functions may occur in a non-cell autonomous fashion, i.e., IL-15Ra expression on cells other than NK cells regulate NK cell functions. Accordingly, we propose to investigate the mechanism(s) by which IL-15Ra regulates NK cell function and development. Specifically, we will determine the roles of IL-15Ra in supporting: (1) NK cell development; (2) mature NK cell homeostasis; and (3) NK cell activation. These experiments should reveal novel insights into which cells use IL-15Ra to supports NK cells in vivo, and how IL-15Ra performs its unusual molecular function.